Almeida Gabriela M, Duarte Tiago L, Farmer Peter B, Steward William P, Jones George D D
Radiation and Oxidative Stress Group, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom.
Int J Cancer. 2008 Apr 15;122(8):1810-9. doi: 10.1002/ijc.23188.
Systemic chemotherapy is extensively used in cancer therapy, however, for many treatments' response rates are limited. Furthermore, certain regimens are frequently associated with significant morbidity and occasional mortality. Consequently, when alternative options exist, it is desirable to reserve a particular chemotherapy for those patients whose tumours will respond. Therefore, attention is turning to the development of techniques that could provide predictive information regarding a tumour's particular chemosensitivity, as a means of enhancing patient selection for that specific treatment. One approach has been to focus on measures of DNA damage formation and repair as being potentially predictive of cancer cell chemosensitivity, the premise being that higher levels of induced DNA damage (resulting from the chemotherapeutic agents) and/or deficiencies in DNA damage repair are indicative of greater sensitivity. In the present study we have investigated the Comet assay response of a panel of non-small cell lung cancer cell lines towards cisplatin and found an inverse correlation between sensitivity and damage formation resulting from this agent. Moreover, an inverse correlation was found between resistance and extent of damage repair. Further analysis of multiple alternate cellular end-points (including cell cycle analysis, apoptosis and gene expression changes) revealed cisplatin damage tolerance to be a chemoresistance mechanism in this model system. This study highlights damage tolerance mechanisms as potentially confounding factors in attempts to develop predictive tests based on measures of genotoxicity. To address this we would argue that a range of multiple end-points should be analysed to ascertain the "complete predictive picture".
全身化疗在癌症治疗中被广泛应用，然而，许多治疗的有效率有限。此外，某些治疗方案常常伴有显著的发病率，偶尔还会导致死亡。因此，当存在其他选择时，最好将特定的化疗方案保留给那些肿瘤会产生反应的患者。所以，人们的注意力正转向开发能够提供有关肿瘤特定化学敏感性预测信息的技术，以此作为增强针对特定治疗的患者选择的一种手段。一种方法是将重点放在DNA损伤形成和修复的测量上，因为它们可能预测癌细胞的化学敏感性，其前提是较高水平的诱导性DNA损伤（由化疗药物引起）和/或DNA损伤修复缺陷表明敏感性更高。在本研究中，我们调查了一组非小细胞肺癌细胞系对顺铂的彗星试验反应，发现敏感性与该药物引起的损伤形成之间呈负相关。此外，耐药性与损伤修复程度之间也呈负相关。对多个其他细胞终点（包括细胞周期分析、凋亡和基因表达变化）的进一步分析表明，顺铂损伤耐受性是该模型系统中的一种化疗耐药机制。这项研究强调损伤耐受机制可能是在试图基于遗传毒性测量开发预测性测试时的混杂因素。为了解决这个问题，我们认为应该分析一系列多个终点，以确定“完整的预测情况”。
